Nitric oxide and the proliferation of vascular smooth muscle cells.

1. Introduction with thiol groups to produce nitrosothiols [9]. Hence, the effects of NO and the pathophysiological influences on it Vascular smooth muscle cell (VSMC) proliferation is an may also be mediated indirectly, potentiated or inhibited important component of vessel wall remodelling in re-through the availability of these oxygen species. Irre-sponse to injury, for example, after angioplasty or vein spective of the physiological role of NO in VSMC prolifer-grafting, and during atherosclerosis formation. Endo-ation, a pharmacological effect of NO may still be thelium-derived nitric oxide (NO) production is both a exploited to reduce neointima formation and prevent tonic and an induced regulator of blood vessel tone [1–3]. adverse vessel-wall remodeling. We will therefore also Its function is impaired by atherosclerosis and, more consider the experience with this approach either in significantly, by atherogenic risk factors, including hy-conventional or gene therapy. percholesterolaemia, homocysteinaemia, diabetes, smoking and high blood pressure, even before the appearance of overt atherosclerosis [4–6] Endothelial NO production is 2. Alterations in NO formation and NO synthases dysfunctional after balloon injury and in vein grafts at the that may influence VSMC proliferation in time when VSMC proliferation and neointima formation is pathological states progressing [5,6]. It has been tempting, therefore, to propose a causal relationship between impaired NO pro-During atherogenesis, VSMCs are activated to a syn-duction and increased VSMC proliferation. If so, this thetic state, which allows them to proliferate and migrate might explain, in part, the association between endothelial to the intima and produce extracellular matrix [10,11]. This dysfunction and atherogenesis. leads to neointima formation and the fibrous component of The primary purpose of this review is to discuss atherosclerosis [12,13]. Atherosclerosis is associated with a critically the evidence to support such an hypothesis. We reduced endothelium-dependent vasodilatation, which has will also go on to consider the molecular mechanisms that been ascribed to reduced NO formation [4,14]. Although might underlie the inhibitory effects of NO on VSMC endothelium-dependent responses are attenuated in aortic proliferation, with the following important caveats. Firstly, tissue from cholesterol-fed rabbits, total arterial NO pro-any direct action of NO on an increase in VSMC numbers duction is actually increased [15]. This increased NO may be mediated at a variety of levels, for example, on the production is likely to be the result of the induction of signal transduction pathways, on energy production or by inducible nitric oxide synthase (iNOS) in VSMCs [16–19]. promoting cell death. …